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The pancreatic innervation undergoes dynamic remodeling during the development of pancreatic ductal adenocarcinoma (PDAC). Denervation experiments have shown that different types of axons can exert either pro- or anti-tumor effects, but conflicting results exist in the literature, leaving the overall influence of the nervous system on PDAC incompletely understood. To address this gap, we propose a continuous mathematical model of nerve-tumor interactions that allows in silico simulation of denervation at different phases of tumor development. This model takes into account the pro- or anti-tumor properties of different types of axons (sympathetic or sensory) and their distinct remodeling dynamics during PDAC development. We observe a "shift effect" where an initial pro-tumor effect of sympathetic axon denervation is later outweighed by the anti-tumor effect of sensory axon denervation, leading to a transition from an overall protective to a deleterious role of the nervous system on PDAC tumorigenesis. Our model also highlights the importance of the impact of sympathetic axon remodeling dynamics on tumor progression. These findings may guide strategies targeting the nervous system to improve PDAC treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The peripheral nervous system is a key regulator of cancer progression. In pancreatic ductal adenocarcinoma (PDAC), the sympathetic branch of the autonomic nervous system inhibits cancer development. This inhibition is associated with extensive sympathetic nerve sprouting in early pancreatic cancer precursor lesions. However, the underlying mechanisms behind this process remain unclear. This study aimed to investigate the roles of pancreatic Schwann cells in the structural plasticity of sympathetic neurons. We examined the changes in the number and distribution of Schwann cells in a transgenic mouse model of PDAC and in a model of metaplastic pancreatic lesions induced by chronic inflammation. Schwann cells proliferated and expanded simultaneously with new sympathetic nerve sprouts in metaplastic/neoplastic pancreatic lesions. Sparse genetic labeling showed that individual Schwann cells in these lesions had a more elongated and branched structure than those under physiological conditions. Schwann cells overexpressed neurotrophic factors, including glial cell-derived neurotrophic factor (GDNF). Sympathetic neurons upregulated the GDNF receptors and exhibited enhanced neurite growth in response to GDNF in vitro. Selective genetic deletion of Gdnf in Schwann cells completely blocked sympathetic nerve sprouting in metaplastic pancreatic lesions in vivo. This study demonstrated that pancreatic Schwann cells underwent adaptive reprogramming during early cancer development, supporting a protective antitumor neuronal response. These finding could help to develop new strategies to modulate cancer associated neural plasticity., (© 2024 The Author(s). GLIA published by Wiley Periodicals LLC.)

Background: Borderline personality disorder (BPD) is a serious disorder with a lifetime prevalence of 2.7-5.9% and is thought to correlate with altered neuroplasticity. The aim of the present study is to investigate possible associations of BPD (-severity) and alterations in neurological soft signs (NSS) and olfactory function., Methods: For the monocentric observational study, 39 female subjects with a BPD diagnosis and 19 female healthy control subjects were recruited. The groups were matched by age. Olfactory functions were examined using Sniffin' Sticks. NSS were assessed by a standardized test with 50 items., Results: BPD subjects have higher NSS scores in group comparison. By contrast, there are no alterations in the total score of olfactory function, while the BPD subjects scored higher in smell identification. Within the BPD group, the total NSS score was discovered to have a negative correlation with olfactory function. BPD subjects taking antipsychotics show more NSS than those without. We found no significant influence of posttraumatic stress disorder on the NSS or olfactory function. The BPD-severity correlates with NSS., Limitations: Due to the cross-sectional design, we did not have a follow up examination. The sample size was small, and all patients had psychiatric comorbidities. Additionally, we did not perform MRI to connect our findings with possible structural abnormalities., Conclusions: Our study confirmed altered NSS in BPD patients, whereas no impairment in the olfactory function was found. Further research is required to establish NSS and smell tests as clinical screening tools in BPD patients and to uncover the disorder's impact on neuroplasticity., Competing Interests: Declaration of competing interest RS took part in an educational event sponsored by Livanova. HF received speaker‘s honararia and served as advisor for Recordati Pharma GmbH and Janssen-Cilag Gmbh. AN received lecture fees from Novartis and Merck. HBM took part in educational events sponsored by Livanova and Rovi. SBe, SH, SDG, LS, FMM, CW, SBl declare no conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: There exists an unfulfilled requirement for effective cochlear pharmacotherapy. Controlled local drug delivery could lead to effective bioavailability. The round window niche (RWN), a cavity in the middle ear, is connected to the cochlea via a membrane through which drug can diffuse. We are developing individualized drug-eluting RWN implants (RNIs). To test their effectiveness in guinea pigs, a commonly used model in cochlear pharmacology studies, it is first necessary to develop guinea pig RNIs (GP-RNI)., Methods: Since guinea pigs do not have a RWN such as it is present in humans and to reduce the variables in in vivo studies, a one-size-fits-all GP-RNI model was designed using 12 data sets of Dunkin-Hartley guinea pigs. The model was 3D-printed using silicone. The accuracy and precision of printing, distribution of the sample ingredient dexamethasone (DEX), biocompatibility, bio-efficacy, implantability and drug release were tested in vitro . The GP-RNI efficacy was validated in cochlear implant-traumatized guinea pigs in vivo ., Results: The 3D-printed GP-RNI was precise, accurate and fitted in all tested guinea pig RWNs. DEX was homogeneously included in the silicone. The GP-RNI containing 1% DEX was biocompatible, bio-effective and showed a two-phase and sustained DEX release in vitro , while it reduced fibrous tissue growth around the cochlear implant in vivo ., Conclusions: We developed a GP-RNI that can be used for precise inner ear drug delivery in guinea pigs, providing a reliable platform for testing the RNI's safety and efficacy, with potential implications for future clinical translation.

To contribute to our understanding of cohort differences and the Flynn effect in the cognitive decline among older Americans, this study aims to compare rates of cognitive decline between two birth cohorts within a study of older Americans and to examine the importance of medical and demographic confounders. Analyses used data from the National Health and Aging Trends Study (2011-2019), which recruited older Americans in 2011 and again in 2015 who were then followed for 5 years. We employed mixed-effect models to examine the linear and quadratic main and interaction effects of year of birth while adjusting for covariates such as annual round, sex/gender, education, race/ethnicity, heart disease, hypertension, diabetes, test unfamiliarity, and survey design. We analyzed data from 11,167 participants: 7,325 from 2011 to 2015 and 3,842 from 2015 to 2019. The cohort recruited in 2015 was born, on average, 5.33 years later than that recruited in 2011 and had higher functioning than the one recruited in 2011 across all observed cognitive domains that persisted after adjusting for covariates. In multivariable-adjusted analyses, a 1-year increase in year of birth was associated with increased episodic memory (β = 0.045, SE = 0.001, p < .001), orientation (β = 0.034, SE = 0.001, p < .001), and executive function (β = 0.036, SE = 0.001, p < .001). Participants born 1 year later had slower rates of decline in episodic memory (β = 0.004, SE = 0.000, p < .001), orientation (β = 0.003, SE = 0.000, p < .001), and executive function (β = 0.001, SE = 0.000, p = .002). Additionally, sex/gender modified this relationship for episodic memory (-0.007, SE = 0.002, p < .001), orientation (-0.005, SE = 0.002, p = .008), and executive function (-0.008, SE = 0.002, p < .001). These results demonstrate the persistence of the Flynn effect in old age across cognitive domains and identified a deceleration in the rate of cognitive decline across cognitive domains. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Objective: To describe the detailed surgical procedure for open-chest CPR (OC-CPR) through a transdiaphragmatic (TD) approach during planned laparotomy and to evaluate the procedure time and damage to organs., Animals: 7 mixed-breed canine cadavers., Methods: The procedure was divided into 3 stages. Durations for each of the 3 stages of the procedure and total time from diaphragmatic incision to the end of Rumel tourniquet application were recorded. Subjective assessment of ease of procedures and postprocedural physical evaluation of thoracoabdominal organs were also performed., Results: Mean time from diaphragmatic incision to pericardiotomy was 15.1 seconds (SD, 4.0). Performing 10 cardiac compressions took 12.0 seconds (SD, 1.8). Dissection of the aorta and application of a Rumel tourniquet took 130.4 seconds (SD, 52.2). The mean total time from start of first procedure to end of last procedure was 157.6 seconds (SD, 21.5). The mean length of diaphragmatic incision was 11.5 cm (SD, 2.2). Lung laceration was identified in one dog, and liver laceration was identified in another dog. The mean ease of pericardiotomy was 10, and application of a Rumel tourniquet was 4 (SD, 1.9). There was no instance of abdominal organs moving into the thoracic cavity during the procedure in any of the dogs., Clinical Relevance: Resuscitation techniques during TD OC-CPR can be performed with acceptable timing and effort, except for aortic Rumel tourniquet application, which was difficult and time consuming. Avoidable damage to thoracoabdominal organs can occur.

Relationships between epigenetic aging markers and psychosocial variables such as socioeconomic status and stress have been well-documented, but are often examined cross-sectionally or retrospectively, and have tended to focus on objective markers of SES or major life events. Here, we examined associations between psychosocial variables, including measures of socioeconomic status and social stress, and epigenetic aging markers in adulthood, using longitudinal data spanning three decades from the Midlife in the United States (MIDUS) study. The largest effects were observed for epigenetic markers of change in health, such as DunedinPACE and GrimAge, and for associations involving education, income, net assets, general social stress, inequality-related stress, and financial stress. Analyses of polygenic indices suggests that at least in the case of education, the link to epigenetic aging cannot be accounted for by common genetic variants., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background and Objectives: Changes in RHD generate variations in protein structure that lead to antigenic variants. The classical model divides them into quantitative (weak and Del) and qualitative (partial D). There are two types of protein antigens: linear and conformational. Computational biology analyses the theoretical assembly of tertiary protein structures and allows us to identify the 'topological' differences between isoforms. Our aim was to determine the theoretical antigenic differences between weak RhD variants compared with normal RhD based on structural analysis using bioinformatic techniques., Materials and Methods: We analysed the variations in secondary structures and hydrophobicity of RHD*01, RHD*01W.1, W2, W3, RHD*09.03.01, RHD*09.04, RHD*11, RHD*15 and RHD*21. We then modelled the tertiary structure and calculated their probable antigenic regions, intra-protein interactions, displacement and membrane width and compared them with Rhce., Results: The 10 proteins are similar in their secondary structure and hydrophobicity, with the main differences observed in the exofacial coils. We identified six potential antigenic regions: one that is unique to RhD (R3), one that is common to all D (R6), three that are highly variable among RhD isoforms (R1, R2 and R4), one that they share with Rhce (R5) and two that are unique to Rhce (Ra and Rbc)., Conclusion: The alloimmunization capacity of these subjects could be explained by the variability of the antigen pattern, which is not necessarily recognized or recognized with lower intensity by the commercially available antibodies, and not because they have a lower protein concentration in the membrane., (© 2024 International Society of Blood Transfusion.)

Hypothesis: Development of a new method for large vestibular aqueduct (LVA)/large endolymphatic sac anomaly (LESA) assessment using magnetic resonance imaging (MRI) and computed tomography (CT)/cone beam CT (CBCT) images. The secondary objective was to compare both modalities., Background: The gold standard for LVA diagnosis is the analysis of CT images using Valvassori and Clemis or Cincinnati criteria. The previous studies showed inconclusive results regarding the correlation between audiological and radiological data., Methods: Retrospective analysis of radiological images from 173 patients (315 ears), who were diagnosed with LVA/LESA based on CT/CBCT and/or MRI images of the temporal bone. The images obtained using both techniques were used to measure the following dimensions of vestibular aqueduct (VA)/endolymphatic duct (ED)/intraosseous endolymphatic sac (ES): width of the opening, length, and width at external aperture. In MRI images, the maximal contact diameters of the extraosseous or intraosseous ES and dura mater were measured as well., Results: LVA has been reported to be bilateral in 82% (142 patients) and unilateral in 18% (31 patients) of cases. Comparison of MRI and CT/CBCT measurements showed a moderate correlation (0.64) in external aperture, a moderate correlation (0.57) in the width of the VA opening, and a weak correlation (0.34) in length measurements (p < 0.05)., Conclusion: We developed a new method to identify the heterogeneous pathology of LVA/LESA using reconstruction along the VA/ED/intraosseous ES axis, three measurements on two planes, and focus on the maximal contact diameter between the extraosseous or intraosseous ES and dura mater., Competing Interests: Conflicts of interest and source of funding: As a first author, I am disclosing that my sister Justina Ivanauskaite is working as a director of data science in Animal Health IT, MSD Czech Republic. The content of our research is not related to the products of MSD, and our partnership on this research is based on our familial relationship. In addition, I received a travel grant from the Cluster of Excellence “Hearing4all” EXC 1077/1, 30625 Hanover, Germany, to attend the ARO MidWinter 2023 meeting. For the remaining authors, none were declared., (Copyright © 2024, Otology & Neurotology, Inc.)

Background and Objectives: Computational biology analyses the theoretical tertiary structure of proteins and identifies the 'topological' differences between RhD and RhCE. Our aim was to identify the theoretical structural differences between the four isoforms of RhCE and RhD using computational biological tools., Materials and Methods: Physicochemical profile was determined by hydrophobicity and electrostatic potential analysis. Secondary and tertiary structures were generated using computational biology tools. The structures were evaluated and validated using Ramachandran algorithm, which calculates the single score, p-value and root mean square deviation (RMSD). Structures were overlaid on local refinement of 'RhAG-RhCE-ANK' (PBDID 7uzq) and RhAG to compare their spatial distribution within the membrane., Results: All proteins differed in surface area and electrostatic distance due to variations in hydrophobicity and electrostatic potential. The RMSD between RhD and RhCE was 0.46 ± 0.04 Å, and the comparison within RhCE was 0.57 ± 0.08 Å. The percentage of amino acids in the hydrophobic thickness was 50.24% for RhD while for RhCE it ranged between 73.08% and 76.68%. The RHAG hydrophobic thickness was 34.2 Å, and RhCE's hydrophobic thickness was 33.83 Å. We suggest that the C/c antigens differ exofacially at loops L1 and L2. For the E/e antigens, the difference lies in L6. By contrast, L4 is the same for all proteins except Rhce., Conclusion: The physicochemical properties of Rh proteins made them different, although their genes are homologous. Using computational biology, we model structures with sufficient precision, similar to those obtained experimentally. An amino acid variation alters the folding of the tertiary structure and the interactions with other proteins, modifying the electrostatic environment, the spatial conformations and therefore the antigenic recognition., (© 2023 International Society of Blood Transfusion.)

Structural and functional deficits in brain connectivity are reported in patients with fetal alcohol spectrum disorders (FASDs), but whether and how prenatal alcohol exposure (PAE) affects axonal development of neurons and disrupts wiring between brain regions is unknown. Here, we develop a mouse model of moderate alcohol exposure during prenatal brain wiring to study the effects of PAE on corpus callosum (CC) development. PAE induces aberrant navigation of interhemispheric CC axons that persists even after exposure ends, leading to ectopic termination in the contralateral cortex. The neuronal miR-17-5p and its target ephrin type A receptor 4 (EphA4) mediate the effect of alcohol on the contralateral targeting of CC axons. Thus, altered microRNA-mediated regulation of axonal guidance may have implications for interhemispheric cortical connectivity and associated behaviors in FASD., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Aims: The liver is an innervated organ that develops a variety of chronic liver disease (CLD). Axon guidance cues (AGCs), of which ephrins, netrins, semaphorins and slits are the main representative, are secreted or membrane-bound proteins that can attract or repel axons through interactions with their growth cones that contain receptors recognizing these messengers. While fundamentally implicated in the physiological development of the nervous system, the expression of AGCs can also be reinduced under acute or chronic conditions, such as CLD, that necessitate redeployment of neural networks., Methods: This review considers the ad hoc literature through the neglected canonical neural function of these proteins that is also applicable to the diseased liver (and not solely their observed parenchymal impact)., Results: AGCs impact fibrosis regulation, immune functions, viral/host interactions, angiogenesis, and cell growth, both at the CLD and HCC levels. Special attention has been paid to distinguishing correlative and causal data in such datasets in order to streamline data interpretation. While hepatic mechanistic insights are to date limited, bioinformatic evidence for the identification of AGCs mRNAs positive cells, protein expression, quantitative regulation, and prognostic data have been provided. Liver-pertinent clinical studies based on the US Clinical Trials database are listed. Future research directions derived from AGC targeting are proposed., Conclusion: This review highlights frequent implication of AGCs in CLD, linking traits of liver disorders and the local autonomic nervous system. Such data should contribute to diversifying current parameters of patient stratification and our understanding of CLD., (© 2023 The Authors. Liver International published by John Wiley & Sons Ltd.)

Objective: To compare the acute strength (failure load and work to failure) of standard incisional gastropexy (SIG) and modified incisional gastropexy (MIG)., Animals: 37 pig cadavers., Procedures: Stomachs and right abdominal walls were harvested from pigs euthanized for reasons unrelated to this study. The tissues were stored in lactated Ringer's solution overnight in a 5 °C cooler. Matching body wall and stomach tissue pairs were randomized and divided into 2 groups, on which either SIG or MIG was performed the following day. The MIG technique was identical to SIG except 2 additional simple interrupted sutures, 1 cranial and 1 caudal to the continuous suture line, were placed full thickness into the stomach to ensure engagement of the submucosa. After gastropexy, the samples underwent biomechanical testing. Information regarding change in position and load was generated by the MTESTQuattro software. Mode of failure was examined after the procedure was complete., Results: The MIG had higher failure load and work to failure compared to SIG. All failures were caused by gastric tissue tearing., Clinical Relevance: The MIG is biomechanically superior to SIG and may provide more security than SIG during healing. However, clinical study is needed to ascertain if there is a difference in gastropexy failure and complications between these 2 techniques.

Objective: To compare complications between a modified incisional gastropexy (MIG) technique and standard incisional gastropexy (SIG)., Animals: 347 client-owned dogs., Procedures: Dogs that had undergone SIG or MIG from March 2005 through April 2019 were identified through a medical record search of the University of Missouri Veterinary Health Center. The MIG technique is identical to SIG except 2 additional simple interrupted sutures are added, 1 cranial and 1 caudal to the continuous suture line, going full thickness into the stomach to ensure engagement of submucosa. Medical record information was used to identify intraoperative, postoperative, and short-term complications, and telephone or email communication to pet owners and/or referring veterinarians was used to identify complications (short-term and long-term) after discontinuance of care at the University of Missouri Veterinary Health Center. Intraoperative, postoperative, short-term, and long-term complications were analyzed in aggregate within 6 matched groupings: (1) gastropexy for gastric dilatation-volvulus, (2) prophylactic gastropexy without other procedures, (3) gastropexy with ovariohysterectomy, (4) gastropexy with castration, (5) gastropexy with splenectomy, and (6) gastropexy with celiotomy other than splenectomy. Overall rates of complications potentially attributed to gastropexy were compared between SIG and MIG using the Fisher exact test. Overall rates of complications not attributed to gastropexy were compared between SIG and MIG using the χ2 test., Results: There were no significant differences in overall complication rates between SIG and MIG., Clinical Relevance: Surgeons who feel that engagement of gastric submucosa is important for gastropexy success may use the MIG technique with minimal fear of complications. However, superiority of one technique over the other cannot be determined on the basis of this study.

The local treatment of diseases by drug-eluting implants is a promising tool to enable successful therapy under potentially reduced systemic side effects. Especially, the highly flexible manufacturing technique of 3D printing provides the opportunity for the individualization of implant shapes adapted to the patient-specific anatomy. It can be assumed that variations in shape can strongly affect the released amounts of drug per time. This influence was investigated by performing drug release studies with model implants of different dimensions. For this purpose, bilayered model implants in a simplified geometrical shape in form of bilayered hollow cylinders were developed. The drug-loaded abluminal part consisted of a suitable polymer ratio of Eudragit ® RS and RL, while the drug-free luminal part composed of polylactic acid served as a diffusion barrier. Implants with different heights and wall thicknesses were produced using an optimized 3D printing process, and drug release was determined in vitro. The area-to-volume ratio was identified as an important parameter influencing the fractional drug release from the implants. Based on the obtained results drug release from 3D printed implants with individual shapes exemplarily adapted to the frontal neo-ostial anatomy of three different patients was predicted and also tested in an independent set of experiments. The similarity of predicted and tested release profiles indicates the predictability of drug release from individualized implants for this particular drug-eluting system and could possibly facilitate the estimation of the performance of customized implants independent of individual in vitro testing of each implant geometry.

The aim of this study was to develop and validate a semi-automated segmentation approach that identifies the round window niche (RWN) and round window membrane (RWM) for use in the development of patient individualized round window niche implants (RNI) to treat inner ear disorders. Twenty cone beam computed tomography (CBCT) datasets of unilateral temporal bones of patients were included in the study. Defined anatomical landmarks such as the RWM were used to develop a customized 3D Slicer™ plugin for semi-automated segmentation of the RWN. Two otolaryngologists (User 1 and User 2) segmented the datasets manually and semi-automatically using the developed software. Both methods were compared in-silico regarding the resulting RWM area and RWN volume. Finally, the developed software was validated ex-vivo in N = 3 body donor implantation tests with additively manufactured RNI. The independently segmented temporal bones of the different Users showed a strong consistency in the volume of the RWN and the area of the RWM. The volume of the semi-automated RWN segmentations were 48 ± 11% smaller on average than the manual segmentations and the area of the RWM of the semi-automated segmentations was 21 ± 17% smaller on average than the manual segmentation. All additively manufactured implants, based on the semi-automated segmentation method could be implanted successfully in a pressure-tight fit into the RWN. The implants based on the manual segmentations failed to fit into the RWN and this suggests that the larger manual segmentations were over-segmentations. This study presents a semi-automated approach for segmenting the RWN and RWM in temporal bone CBCT scans that is efficient, fast, accurate, and not dependent on trained users. In addition, the manual segmentation, often positioned as the gold-standard, actually failed to pass the implantation validation.

Objective: To report the management and outcomes of dogs treated for lower esophageal sphincter achalasia-like syndrome (LES-AS) with modified Heller myotomy, Dor fundoplication, and with the use of a temporary gastrostomy tube., Study Design: Retrospective., Sample Population: Thirteen client-owned dogs., Methods: Medical records and a client survey were used to assess frequency of vomiting/regurgitation, quality of life (QoL), bodyweight, and feeding modifications at the following time points: prior to referral, postoperatively from discharge to first recheck (4-6 weeks), and from first recheck to survey (48 months). Postoperative and gastrostomy tube complications were surveyed and recorded. Pretreatment and 4-6 weeks postoperative videofluoroscopic swallow studies (VFSS) were compared. Two-sided t-tests were used to compare outcomes between survey time points., Results: Postoperative VFSS scores (available in 9 dogs) improved over preoperative scores in 6 dogs, and 12/13 dogs survived to discharge. One dog was euthanized 3 days postoperatively due to aspiration pneumonia. Postoperative gastrostomy tube complications occurred in half of the dogs that survived to discharge. According to the owners, scores assigned to vomiting/regurgitation improved by 180% (P = .004), QoL by 100% (P = .004), and bodyweight by 63% (P = .035)., Conclusion: Modified Heller myotomy with Dor fundoplication and the use of a temporary gastrostomy tube improved clinical signs and owners' perceived quality of life in half of the dogs treated for LES-AS in our clinical setting. Oral sildenafil therapy discontinued postoperatively suggests that surgery was equally efficacious., Clinical Significance: Modified Heller myotomy with Dor fundoplication and temporary gastrostomy tube is a treatment option with potentially sustained benefits for dogs that have LES-AS., (© 2022 American College of Veterinary Surgeons.)

The nervous system is today recognized to play an important role in the development of cancer. Indeed, neurons extend long processes (axons) that grow and infiltrate tumors in order to regulate the progression of the disease in a positive or negative way, depending on the type of neuron considered. Mathematical modeling of this biological process allows to formalize the nerve-tumor interactions and to test hypotheses in silico to better understand this phenomenon. In this work, we introduce a system of differential equations modeling the progression of pancreatic ductal adenocarcinoma (PDAC) coupled with associated changes in axonal innervation. The study of the asymptotic behavior of the model confirms the experimental observations that PDAC development is correlated with the type and densities of axons in the tissue. We study then the identifiability and the sensitivity of the model parameters. The identifiability analysis informs on the adequacy between the parameters of the model and the experimental data and the sensitivity analysis on the most contributing factors on the development of cancer. It leads to significant insights on the main neural checkpoints and mechanisms controlling the progression of pancreatic cancer. Finally, we give an example of a simulation of the effects of partial or complete denervation that sheds lights on complex correlation between the healthy, pre-cancerous and cancerous cell densities and axons with opposite functions., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Purpose: Loneliness is associated with poor health including premature mortality. There are cross-sectional associations with depression, anxiety, psychosis, and other mental health outcomes. However, it is not known whether loneliness is causally linked with the new onset of mental health problems in the general population. Longitudinal studies are key to understanding this relationship. We synthesized evidence from longitudinal studies investigating the relationship between loneliness and new onset of mental health problems, in the general population., Method: We systematically searched six electronic databases, unpublished sources, and hand-searched references, up to August 2021. We conducted a meta-analysis of eight independent cohorts and narrative synthesis of the remaining studies., Results: We included 32 studies, of which the majority focused on depression. Our narrative synthesis found most studies show loneliness at baseline which is associated with the subsequent new onset of depression. The few studies on anxiety and self-harm also showed a positive association. Our meta-analysis found a pooled adjusted odds ratio of 2.33 (95% CI 1.62-3.34) for risk of new onset depression in adults who were often lonely compared with people who were not often lonely. This should be interpreted with caution given evidence of heterogeneity., Conclusion: Loneliness is a public mental health issue. There is growing evidence it is associated with the onset of depression and other common mental health problems. Future studies should explore its impact across the age range and in more diverse populations, look beyond depression, and explore the mechanisms involved with a view to better informing appropriate interventions., (© 2022. The Author(s).)

Postoperative restenosis in patients with external ear canal (EEC) atresia or stenosis is a common complication following canaloplasty. Our aim in this study was to explore the feasibility of using a three dimensionally (3D)-printed, patient-individualized, drug ((dexamethasone (DEX)), and ciprofloxacin (cipro))-releasing external ear canal implant (EECI) as a postoperative stent after canaloplasty. We designed and pre-clinically tested this novel implant for drug release (by high-performance liquid chromatography), biocompatibility (by the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay), bio-efficacy (by the TNF-α (tumor necrosis factor-alpha)-reduction test (DEX) and inhibition zone test (for cipro)), and microbial contamination (formation of turbidity or sediments in culture medium). The EECI was implanted for the first time to one patient with a history of congenital EEC atresia and state after three canaloplasties due to EEC restenosis. The preclinical tests revealed no cytotoxic effect of the used materials; an antibacterial effect was verified against the bacteria Staphylococcus aureus and Pseudomonas aeruginosa , and the tested UV-irradiated EECI showed no microbiological contamination. Based on the test results, the combination of silicone with 1% DEX and 0.3% cipro was chosen to treat the patient. The EECI was implantable into the EEC; the postoperative follow-up visits revealed no otogenic symptoms or infections and the EECI was explanted three months postoperatively. Even at 12 months postoperatively, the EEC showed good epithelialization and patency. Here, we report the first ever clinical application of an individualized, drug-releasing, mechanically flexible implant and suggest that our novel EECI represents a safe and effective method for postoperatively stenting the reconstructed EEC.

The neurotransmitter dopamine (DA) controls multiple behaviors and is perturbed in several major brain diseases. DA is released from large populations of specialized structures called axon varicosities. Determining the DA release mechanisms at such varicosities is essential for a detailed understanding of DA biology and pathobiology but has been limited by the low spatial resolution of DA detection methods. We used a near-infrared fluorescent DA nanosensor paint, adsorbed nanosensors detecting release of dopamine (AndromeDA), to detect DA secretion from cultured murine dopaminergic neurons with high spatial and temporal resolution. We found that AndromeDA detects discrete DA release events and extracellular DA diffusion and observed that DA release varies across varicosities. To systematically detect DA release hotspots, we developed a machine learning–based analysis tool. AndromeDA permitted the simultaneous visualization of DA release for up to 100 dopaminergic varicosities, showing that DA release hotspots are heterogeneous and occur at only ∼17% of all varicosities, indicating that many varicosities are functionally silent. Using AndromeDA, we determined that DA release requires Munc13-type vesicle priming proteins, validating the utility of AndromeDA as a tool to study the molecular and cellular mechanism of DA secretion.

VPS35 is a core component of the retromer complex involved in familial forms of neurodegenerative diseases such as Parkinson's and Alzheimer's disease. In mice, VPS35 is expressed during early brain development. However, previous studies have reported that VPS35 activity is largely dispensable for normal neuronal development and initial elaboration of axonal projections. Here, we evaluated the role of VPS35 in the mouse embryonic brain using two Cre-driver lines that remove Vps35 from the cortex at different prenatal stages. We found that Vps35 mutant mice displayed microcephaly and decreased cortical thickness from the embryonic stages to adulthood. VPS35 also regulates cortical development by affecting a subpopulation of neural progenitor cells and the survival of postmitotic neurons. In addition, we showed that a lack of VPS35 leads to hypoplasia and misrouting of several axonal projections, including the anterior commissure and fornix. Furthermore, VPS35 deficiency impairs the non-autonomous development of thalamocortical axons (TCAs), which show severe disruption of innervation and terminal arborization in the cortex. Together, these data demonstrate that VPS35 plays a greater role in embryonic development of the mammalian brain than it was previously thought., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Given the links between the built environment and loneliness, there is interest in using place-based approaches (addressing built environment characteristics and related socio-spatial factors) in local communities to tackle loneliness and mental health problems. However, few studies have described the effectiveness, acceptability, or potential harms of such interventions. This review aimed to synthesize the literature describing local community-based interventions that target place-based factors to address loneliness and mental health problems, informing the development of future public health approaches. We searched PsycINFO, Medline, and Embase using a structured search strategy to identify English-language studies evaluating the effectiveness, acceptability, and potential harms of place-based community interventions in addressing loneliness and mental health problems, both in general and clinical populations. Seven studies met the inclusion criteria, classified as evaluating provision of community facilities (such as clubhouses), active engagement in local green spaces, and housing regeneration. None were randomised trials. Quantitative and qualitative findings suggested promising effects and/or acceptability of six interventions, with minimal potential harms. There is a clear need for randomised trials or quasi-experimental studies of place-based interventions to describe their effectiveness in addressing loneliness and mental health problems, as well as complementary qualitative work investigating acceptability. This will inform future policy development.

Neuronal nerve processes in the tumor microenvironment were highlighted recently. However, the origin of intra-tumoral nerves remains poorly known, in part because of technical difficulties in tracing nerve fibers via conventional histological preparations. Here, we employ three-dimensional (3D) imaging of cleared tissues for a comprehensive analysis of sympathetic innervation in a murine model of pancreatic ductal adenocarcinoma (PDAC). Our results support two independent, but coexisting, mechanisms: passive engulfment of pre-existing sympathetic nerves within tumors plus an active, localized sprouting of axon terminals into non-neoplastic lesions and tumor periphery. Ablation of the innervating sympathetic nerves increases tumor growth and spread. This effect is explained by the observation that sympathectomy increases intratumoral CD163 + macrophage numbers, which contribute to the worse outcome. Altogether, our findings provide insights into the mechanisms by which the sympathetic nervous system exerts cancer-protective properties in a mouse model of PDAC., (© 2022. The Author(s).)

Gut dysbiosis has been associated with intestinal and extraintestinal malignancies, but whether and how carcinogenesis drives compositional shifts of the microbiome to its own benefit remains an open conundrum. Here, we show that malignant processes can cause ileal mucosa atrophy, with villous microvascular constriction associated with dominance of sympathetic over cholinergic signaling. The rapid onset of tumorigenesis induced a burst of REG3γ release by ileal cells, and transient epithelial barrier permeability that culminated in overt and long-lasting dysbiosis dominated by Gram-positive Clostridium species. Pharmacologic blockade of β-adrenergic receptors or genetic deficiency in Adrb2 gene, vancomycin, or cohousing of tumor bearers with tumor-free littermates prevented cancer-induced ileopathy, eventually slowing tumor growth kinetics. Patients with cancer harbor distinct hallmarks of this stress ileopathy dominated by Clostridium species. Hence, stress ileopathy is a corollary disease of extraintestinal malignancies requiring specific therapies., Significance: Whether gut dysbiosis promotes tumorigenesis and how it controls tumor progression remain open questions. We show that 50% of transplantable extraintestinal malignancies triggered a β-adrenergic receptor-dependent ileal mucosa atrophy, associated with increased gut permeability, sustained Clostridium spp.-related dysbiosis, and cancer growth. Vancomycin or propranolol prevented cancer-associated stress ileopathy. This article is highlighted in the In This Issue feature, p. 873., (©2021 American Association for Cancer Research.)

Dexamethasone is widely used in preclinical studies and clinical trials to treat inner ear disorders. The results of those studies vary widely, maybe due to the different dexamethasone formulations used. Laboratory (lab) and medical grade (med) dexamethasone (DEX, C 22 H 29 FO 5 ) and dexamethasone dihydrogen phosphate-disodium (DPS, C 22 H 28 FNa 2 O 8 P) were investigated for biocompatibility and bio-efficacy in vitro. The biocompatibility of each dexamethasone formulation in concentrations from 0.03 to 10,000 µM was evaluated using an MTT assay. The concentrations resulting in the highest cell viability were selected to perform a bio-efficiency test using a TNFα-reduction assay. All dexamethasone formulations up to 900 µM are biocompatible in vitro. DPS-lab becomes toxic at 1000 µM and DPS-med at 2000 µM, while DEX-lab and DEX-med become toxic at 4000 µM. Bio-efficacy was evaluated for DEX-lab and DPS-med at 300 µM, for DEX-med at 60 µM, and DPS-lab at 150 µM, resulting in significantly reduced expression of TNFα, with DPS-lab having the highest effect. Different dexamethasone formulations need to be applied in different concentration ranges to be biocompatible. The concentration to be applied in future studies should carefully be chosen based on the respective dexamethasone form, application route and duration to ensure biocompatibility and bio-efficacy.

Objective: High levels of psychological distress increase the risk of a wide range of medical diseases. In this study, we investigated the association between posttraumatic stress disorder (PTSD) and kidney disease., Methods: World Trade Center (WTC) responders were included if they had two or more measures of estimated glomerular filtration rate (eGFR). The PTSD Checklist (PCL) was used to define no PTSD (PCL < 40), "mild" PTSD (40 ≤ PCL <50), and "severe" PTSD (PCL ≥50). Subtypes of PTSD by symptom clusters were analyzed. Multinomial logistic regression was used to estimate the association of PTSD with two GFR change outcomes (decline or increase) compared with the stable GFR outcome., Results: In 2266 participants, the mean age was 53.1 years, 8.2% were female, and 89.1% were White. Individuals with PTSD (n = 373; 16.5%) did not differ in mean baseline GFR from individuals without PTSD (89.73 versus 90.56 mL min-1 1.73 m-2; p = .29). During a 2.01-year mean follow-up, a mean GFR decline of -1.51 mL min-1 1.73 m-2 per year was noted. In multivariable-adjusted models, PTSD was associated with GFR decline (adjusted relative risk [aRR] = 1.74 [1.32-2.30], p < .001) compared with stable GFR, with "hyperarousal" symptoms showing the strongest association (aRR =2.11 [1.40-3.19]; p < .001). Dose-response effects were evident when comparing mild with severe PTSD and comparing PTSD with versus without depression. PTSD was also associated with GFR rise (aRR = 1.47 [1.10-1.97], p < .009). The association between PTSD and GFR change was stronger in participants older than 50 years., Conclusions: PTSD may be a novel risk factor for exaggerated longitudinal GFR change in young, healthy adults. These findings need to be validated in other cohorts., (Copyright © 2021 by the American Psychosomatic Society.)

Modern production systems can benefit greatly from integrated and up-to-date digital representations. Their applications range from consistency checks during the design phase to smart manufacturing to maintenance support. Such digital twins not only require data, information and knowledge as inputs but can also be considered integrated models themselves. This paper provides an overview of data, information and knowledge typically available throughout the lifecycle of production systems and the variety of applications driven by data analysis, expert knowledge and knowledge-based systems. On this basis, we describe the potential for combining data analysis and knowledge-based systems in the context of production systems and describe two feasibility studies that demonstrate how knowledge-based systems can be created using data analysis. This article is part of the theme issue 'Towards symbiotic autonomous systems'.

Studies have reported that the age-adjusted incidence of cognitive impairment and dementia may have decreased over the past two decades. Aging is the predominant risk factor for Alzheimer's disease and related dementias and for neurocognitive decline. However, aging cannot explain changes in overall age-adjusted incidence of dementia. The objective of this position paper was to describe the potential for cohort and period effects in cognitive decline and incidence of dementia. Cohort effects have long been reported in demographic literature, but starting in the early 1980s, researchers began reporting cohort trends in cognitive function. At the same time, period effects have emerged in economic factors and stressors in early and midlife that may result in reduced cognitive dysfunction. Recognizing that aging individuals today were once children and adolescents, and that research has clearly noted that childhood cognitive performance is a primary determinant of old-age cognitive performance, this is the first study that proposes the need to connect known cohort effects in childhood cognition with differences in late-life functioning.

Little is known about the characteristics and causes of early-onset cognitive impairment. Responders to the 2001 New York World Trade Center disaster represent an ageing population that was recently shown to have an excess prevalence of cognitive impairment. Neuroimaging and molecular data demonstrate that a subgroup of affected responders may have a unique form of parietal-dominant Alzheimer's Disease. Recent neuropsychological testing and artificial intelligence approaches have emerged as methods that can be used to identify and monitor subtypes of cognitive impairment. We utilized data from World Trade Center responders participating in a health monitoring program and applied a deep learning approach to evaluate neuropsychological and neuroimaging data to generate a cortical atrophy risk score. We examined risk factors associated with the prevalence and incidence of high risk for brain atrophy in responders who are now at midlife. Training was conducted in a randomly selected two-thirds sample ( N  = 99) enrolled using of the results of a structural neuroimaging study. Testing accuracy was estimated for each training cycle in the remaining third subsample. After training was completed, the scoring methodology that was generated was applied to longitudinal data from 1441 World Trade Center responders. The artificial neural network provided accurate classifications of these responders in both the testing (Area Under the Receiver Operating Curve, 0.91) and validation samples (Area Under the Receiver Operating Curve, 0.87). At baseline and follow-up, responders identified as having a high risk of atrophy ( n  =   378) showed poorer cognitive functioning, most notably in domains that included memory, throughput, and variability as compared to their counterparts at low risk for atrophy ( n  =   1063). Factors associated with atrophy risk included older age [adjusted hazard ratio, 1.045 (95% confidence interval = 1.027-1.065)], increased duration of exposure at the WTC site [adjusted hazard ratio, 2.815 (1.781-4.449)], and a higher prevalence of post-traumatic stress disorder [aHR, 2.072 (1.408-3.050)]. High atrophy risk was associated with an increased risk of all-cause mortality [adjusted risk ratio, 3.19 (1.13-9.00)]. In sum, the high atrophy risk group displayed higher levels of previously identified risk factors and characteristics of cognitive impairment, including advanced age, symptoms of post-traumatic stress disorder, and prolonged duration of exposure to particulate matter. Thus, this study suggests that a high risk of brain atrophy may be accurately monitored using cognitive data., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Low-noise quantum frequency conversion in periodically poled nonlinear crystals has proved challenging when the pump wavelength is shorter than the target wavelength. This is-at least in large part-a consequence of the parasitic spontaneous parametric downconversion of pump photons, whose efficiency is increased by fabrication errors in the periodic poling. Here we characterize the poling quality of commercial periodically poled bulk potassium titanyl phosphate (ppKTP) by measuring the sum-frequency generation (SFG) efficiency over a large phase mismatch range from 0 to more than 400 π . Over the probed range, the SFG efficiency behaves nearly ideally and drops to a normalized efficiency of 10 -6 . Our results demonstrate that any background pedestal that would be formed by random duty-cycle errors in ppKTP is substantially reduced when compared to periodically poled lithium niobate. The standard deviation of the random duty-cycle errors can be estimated to be smaller than 2% of the domain length. From this, we expect a noise spectral density that is at least 1 order of magnitude smaller than that of current state-of-the-art single-step frequency converters.

Objective: To determine whether ease of access to thoracic structures for performing open-chest cardiopulmonary resuscitation (OC-CPR) differed between fourth and fifth intercostal space (ICS) left lateral thoracotomies in dogs, and to determine if "shingling" improved access for OC-CPR manipulations., Design: Prospective single-blinded study., Setting: Laboratory., Animals: Twelve mixed breed canine cadavers weighing approximately 20 kg., Interventions: Left lateral thoracotomies were performed at the 4th ICS (n = 6) or 5th ICS (n = 6). Shingling at the 4th or 5th ICS, as applicable, was performed after initial data collection and outcomes were reassessed., Measurements and Main Results: Three evaluators blinded to the surgical approach scored the following parameters on a 0 to 10 scale (0 = easiest, 10 = most difficult): ease of access of the phrenicopericardial ligament, ease of pericardial incision, ease of appropriate hand position, ease of aortic access, ease of Rumel tourniquet application, and ease of proper placement of defibrillation paddles. Objective measurements (time to completion or number of attempts) were made for all but ease of pericardial incision and ease of appropriate hand position. Outcomes were reassessed after shingling. The 5th ICS was superior for ease of aortic access (P = 0.042), time to visualization of aorta (P = 0.009), and ease of application of a Rumel tourniquet (P = 0.019). When comparing scores pre- and post-shingling, shingling improved time to visualization of the aorta (P < 0.001), time to placement of Rumel tourniquet (P < 0.001), ease of paddle placement (P = 0.017), and time to paddle placement (P < 0.001)., Conclusions: Either 4th or 5th ICS thoracotomy may provide adequate access to intrathoracic structures pertinent to performing OC-CPR in dogs weighing approximately 20 kg, but 5th ICS was preferred for most manipulations, and shingling improved access for most of the measured parameters., (© 2021 The Authors. Journal of Veterinary Emergency and Critical Care published by Wiley Periodicals LLC on behalf of Veterinary Emergency and Critical Care Society.)

We present a study performed on 54 unrelated subjects, with and without thalassemic features. Two primer pairs were proposed to perform Sanger sequencing of the complete HBB gene. The bioinformatic analysis was performed taking advantage of the availability of free online tools. In the sample, we found 11 variants, 10 reported, and one novel. Among the variants found, six are clinically important: three encode a premature stop codon [codon 39 (C>T) ( HBB : c.118C>T); IVS-II-1 (G>A) ( HBB : c.315+1G>A), and one not reported], a double substitution within the same allele [Hb Borås ( HBB : c.266T>G) and Hb Santa Giusta Sardegna ( HBB : c.282T>C)], and one whose pathogenicity is not yet defined [Hb Fannin-Lubbock I ( HBB : c.359G>A)]. Even though the variants Hb Borås and Hb Santa Giusta Sardegna have been described, there is no report of their combined occurrence on the same allele, which could cause hemolytic anemia. Although the p.Leu88Arg and p.Cys93Trp variants do not alter the final length of the protein, the bioinformatic results suggest that there are differences in the tertiary structure of β-globin genes, mainly affecting helices E and F, being the motifs of interaction with the heme group. The novel variant is a 4 bp insertion that modifies the open reading frame, changing the last amino acid residue and causing a premature stop codon ( HBB : c.291-294insGCAC). The variant was associated with β-thalassemia (β-thal). Bioinformatic analysis made it possible to predict the consequences that the new variant of the HBB gene caused on the β-globin tertiary structure.

Background: Loneliness is experienced by a third of older adults in the UK and is a modifiable potential risk factor for depressive symptoms. It is unclear how the association between loneliness and depressive symptoms persists over time, and whether it is independent of related social constructs and genetic confounders. We aimed to investigate the association between loneliness and depressive symptoms, assessed on multiple occasions during 12 years of follow-up, in a large, nationally representative cohort of adults aged 50 years and older in England., Methods: We did a longitudinal study using seven waves of data that were collected once every 2 years between 2004 and 2017, from adults aged 50 years and older in the English Longitudinal Study of Ageing (ELSA). The exposure was loneliness at baseline (wave two), measured with the short 1980 revision of the University of California, Los Angeles Loneliness Scale (R-UCLA). The primary outcome was a score indicating severity of depression measured at six subsequent timepoints (waves three to eight), using the eight-item version of the Centre for Epidemiologic Studies Depression Scale (CES-D). Analyses were linear multilevel regressions, before and after adjusting for social isolation, social support, polygenic risk scores, and other sociodemographic and health-related confounders. The secondary outcome was depression diagnosis, measured using a binary version of the CES-D., Findings: 4211 (46%) of 9171 eligible participants had complete data on exposure, outcome, and confounders, and were included in our complete case sample. After all adjustments, a 1-point increase in loneliness score was associated with a 0·16 (95% CI 0·13-0·19) increase in depressive symptom severity score (averaged across all follow-ups). We estimated a population attributable fraction for depression associated with loneliness of 18% (95% CI 12-24) at 1 year of follow-up and 11% (3-19) at the final follow-up (wave eight), suggesting that 11-18% of cases of depression could potentially be prevented if loneliness were eliminated. Associations between loneliness and depressive symptoms remained after 12 years of follow-up, although effect sizes were smaller with longer follow-up., Interpretation: Irrespective of other social experiences, higher loneliness scores at baseline were associated with higher depression symptom severity scores during 12 years of follow-up among adults aged 50 years and older. Interventions that reduce loneliness could prevent or reduce depression in older adults, which presents a growing public health problem worldwide., Funding: National Institute on Aging and a consortium of UK Government departments coordinated by the National Institute for Health Research., (Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Objectives: Medication safety incidents are common in primary care and contributory factors frameworks can assist in our understanding of their causes. A framework that is positioned from the perspective of patients would be advantageous in practice when seeking patient insights into medication safety. The aim of this study was to develop a patient-centered contributory factors framework for examining medication safety incidents., Methods: A purposive sample of 106 members of the public, patients, and carers were recruited to take part in focus groups (n = 18). Focus groups were audio recorded, transcribed, and analyzed using a thematic framework. A patient and public involvement group was set up to undertake multiple roles in the research process, including the development of the focus group schedule, analysis of the data, and the construction of a patient-centered framework of contributory factors (patient-centered medication safety) and implementation checklist., Results: The findings highlighted the importance of communication, supplies of medication and appliances, patient- and carer-related factors, healthcare professional factors, and computer systems and programs in the safe use of medicines. Some contributory factors were unique to primary care patients such as access to services and continuity of care. In conjunction with a patient and public involvement group, a framework of factors that patients believe contribute to medication safety incidents in primary care was developed that could be used by patients and healthcare professionals., Conclusions: The patient-centered medication safety framework and implementation checklist provides a novel tool to examine contributory factors that can lead to medication safety incidents from patients' perspective.

Male ithomiine butterflies (Nymphalidae: Danainae) have hairpencils on the forewings (i.e., androconia) that disseminate semiochemicals during courtship. While most ithomiines are known to contain derivatives of pyrrolizidine alkaloids, dihydropyrrolizines, or γ-lactones in these androconia, here we report on a new class of fatty acid esters identified in two subspecies, Ithomia salapia aquinia and I. s. derasa. The major components were identified as isoprenyl (3-methyl-3-butenyl) ( Z )-3-acetoxy-11-octadecenoate, isoprenyl ( Z )-3-acetoxy-13-octadecenoate ( 12 ) and isoprenyl 3-acetoxyoctadecanoate ( 11 ) by GC/MS and GC/IR analyses, microderivatizations, and synthesis of representative compounds. The absolute configuration of 12 was determined to be R . The two subspecies differed not only in the composition of the ester bouquet, but also in the composition of more volatile androconial constituents. While some individuals of I. s. aquinia contained ithomiolide A ( 3 ), a pyrrolizidine alkaloid derived γ-lactone, I. s. derasa carried the sesquiterpene α-elemol ( 8 ) in the androconia. These differences might be important for the reproductive isolation of the two subspecies, in line with previously reported low gene exchange between the two species in regions where they co-occur. Furthermore, the occurrence of positional isomers of unsaturated fatty acid derivatives indicates activity of two different desaturases within these butterflies, Δ9 and Δ11, which has not been reported before in male Lepidoptera., (Copyright © 2020, Mann et al.; licensee Beilstein-Institut.)

Aims: To compare the duration of anaesthesia, surgery, and postoperative hospitalisation, the proportion of tumours excised with complete histologic margins and immediate postoperative surgical site complications in dogs undergoing removal of cutaneous or subcutaneous soft tissue sarcomas (STS) by either carbon dioxide (CO 2 ) laser or non-laser surgical excision methods. Methods: Medical records of dogs that underwent surgical excision of cutaneous and subcutaneous STS at the University of Missouri between December 2004 and May 2018 were evaluated. The study population consisted of client-owned dogs that underwent CO 2 laser (n = 4) or non-laser (n = 20) excision of a single STS. Data recorded included: signalment, duration of anaesthesia, surgery and postoperative hospitalisation, tumour characteristics, completeness of histologic margins, postoperative complications, adjunctive therapy, and other procedures at the time of surgery. Results: There was no evidence of a difference in mean age, body weight or tumour size between groups. Similarly there was no evidence of a difference in the duration of anaesthesia or surgery, or in the proportion of dogs whose STS were removed with complete histologic margins between dogs whose STS was removed using laser or non-laser surgical excision methods. However, the duration of postoperative hospitalisation trended towards being longer for the laser excision group (p = 0.061). Conclusions: These data provide preliminary evidence that excision of cutaneous or subcutaneous STS with CO 2 surgical laser is comparable to non-laser methods for the measured outcomes.

Loneliness is a common and debilitating problem in individuals with mental health disorders. However, our knowledge on severity of loneliness in different mental health diagnostic groups and factors associated with loneliness is poor, thus limiting the ability to target and improve loneliness interventions. The current study investigated the association between diagnoses and loneliness and explored whether psychological and social factors were related to loneliness. This study employed a cross-sectional design using data from a completed study which developed a measure of social inclusion. It included 192 participants from secondary, specialist mental health services with a primary diagnosis of psychotic disorders (n = 106), common mental disorders (n = 49), or personality disorders (n = 37). The study explored differences in loneliness between these broad diagnostic groups, and the relationship to loneliness of: affective symptoms, social isolation, perceived discrimination, and internalized stigma. The study adhered to the STROBE checklist for observational research. People with common mental disorders (MD = 3.94, CI = 2.15 to 5.72, P < 0.001) and people with personality disorders (MD = 4.96, CI = 2.88 to 7.05, P < 0.001) reported higher levels of loneliness compared to people with psychosis. These differences remained significant after adjustment for all psychological and social variables. Perceived discrimination and internalized stigma were also independently associated with loneliness and substantially contributed to a final explanatory model. The severity of loneliness varies between different mental health diagnostic groups. Both people with common mental disorders and personality disorders reported higher levels of loneliness than people with psychosis. Addressing perceived mental health discrimination and stigma may help to reduce loneliness., (© 2020 Australian College of Mental Health Nurses Inc.)

Objective: Subthreshold psychosis risk symptoms in the general population may be associated with molecular genetic risk for psychosis. This study sought to optimize the association of risk symptoms with genetic risk for psychosis in a large population-based cohort in the UK (N = 9104 individuals 18-65 years of age) by properly accounting for population stratification, factor structure, and sex., Methods: The newly expanded Generation Scotland: Scottish Family Health Study includes 5391 females and 3713 males with age M [SD] = 45.2 [13] with both risk symptom data and genetic data. Subthreshold psychosis symptoms were measured using the Schizotypal Personality Questionnaire-Brief (SPQ-B) and calculation of polygenic risk for schizophrenia was based on 11 425 349 imputed common genetic variants passing quality control. Follow-up examination of other genetic risks included attention-deficit hyperactivity disorder (ADHD), autism, bipolar disorder, major depression, and neuroticism., Results: Empirically derived symptom factor scores reflected interpersonal/negative symptoms and were positively associated with polygenic risk for schizophrenia. This signal was largely sex specific and limited to males. Across both sexes, scores were positively associated with neuroticism and major depressive disorder., Conclusions: A data-driven phenotypic analysis enabled detection of association with genetic risk for schizophrenia in a population-based sample. Multiple polygenic risk signals and important sex differences suggest that genetic data may be useful in improving future phenotypic risk assessment., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: To compare the durations of surgery and anesthesia and the likelihoods of short- and long-term postoperative complications between cats positioned in sternal recumbency versus dorsal recumbency for perineal urethrostomy (PU)., Animals: 247 client-owned cats that underwent PU between January 2004 and December 2015 at 6 veterinary teaching hospitals and 1 private veterinary referral hospital., Procedures: Medical records were reviewed, and signalment, presenting complaints, previous history of urethral obstruction or PU, diet fed, medications administered, indication for PU, durations of surgery and anesthesia for PU, suture type and size, suture pattern for skin closure, and short- and long-term postoperative complications were recorded. Univariable and multivariable analyses were performed to identify differences in durations of surgery and anesthesia and the likelihoods of short- and long-term complications between cats positioned in sternal recumbency and those positioned in dorsal recumbency., Results: Patient position was not associated with durations of surgery and anesthesia for PU, even if a concurrent cystotomy was necessary or the patient required repositioning from sternal to dorsal recumbency. Likewise, patient position was not associated with the likelihood of short- and long-term complications., Conclusions and Clinical Relevance: The observed lack of differences in outcomes between sternal and dorsal recumbency suggested that logistic considerations and personal preference can continue to guide veterinarians when positioning cats for PU.

Case Description: A 10-year-old 7-kg (15.4-lb) neutered male Shih Tzu was referred for evaluation because of a sudden onset of dullness and intermittent vomiting of 1 to 2 weeks' duration. Two days prior to evaluation, clinical signs had worsened and 1 seizure was reported., Clinical Findings: A 3.5 × 2.5-cm soft, dome-shaped mass of the right occipital region of the head was noted on physical examination. Radiography and CT confirmed the presence of the mass and indicated its intra- and extracranial expansion. The MRI images showed compression of the cerebellum by the mass, with distinct margins of hypointensity on both T1- and T2-weighted images., Treatment and Outcome: Surgery was performed, and the mass was completely excised. The dog had mild ataxia, hypermetria, and head tremors after surgery. Histologic examination of the mass yielded a diagnosis of intradiploic epidermoid cyst. On examination 3 weeks after surgery, the previous neurologic signs had resolved. On examination 25 months after surgery, the dog remained free of clinical signs., Clinical Relevance: The present report described the clinical signs, diagnostic imaging results, and successful surgical removal of an intradiploic epidermoid cyst in a dog. Long-term prognosis may be good with complete removal of intradiploic epidermoid cysts in dogs.

An abrupt balance impairment, including leaning, falling, and rolling, occurred after IV administration of 0.2 mg/kg midazolam as a preanesthetic medication in two geriatric dogs with a history of nystagmus and head tilt. In the second case, leaning, falling, and rolling recurred after recovery from general anesthesia but gradually ceased after IV administration of 0.01 mg/kg flumazenil. These two cases suggest that the IV administration of midazolam was responsible for the balance impairment in dogs who were suspected to have idiopathic peripheral vestibular disease.

Purpose: Loneliness is an important issue for mental health service users. However, it has not been a particularly prominent focus of recent mental health research. This paper aimed to explore the severity of loneliness among people leaving mental health community crisis services, and to identify factors associated with loneliness., Methods: A total of 399 participants experiencing mental health crises recruited for a research trial from community crisis services were included in this cross-sectional study. They completed the eight-item measure of the University of California at Los Angeles Loneliness Scale and a set of instruments assessing socio-demographic, psychosocial, and psychiatric variables., Results: Severity of loneliness was high among people leaving community crisis services. Longer years since first contact with mental health services (2-10 years, coefficient = 1.83, 95% CI 0.49-3.16; more than 10 years, coefficient = 1.91, 95% CI 0.46-3.36) and more severe affective symptoms (coefficient = 0.32, 95% CI 0.23-0.40) were associated with greater loneliness, whereas bigger social network size (coefficient = - 0.56, 95% CI - 0.76 to - 0.36) and greater social capital (coefficient = - 0.16, 95% CI - 0.31 to - 0.003) were associated with less severe loneliness., Conclusions: This paper supports a view that people experiencing mental health crises often report relatively severe loneliness, and that loneliness tends to become more severe during the course of illness. A greater awareness of loneliness among mental health professionals may be beneficial. Loneliness is a potential focus of the development of interventions to improve the lives and outcomes of people with significant mental health problems.

Purpose: Subjective and objective social isolation are important factors contributing to both physical and mental health problems, including premature mortality and depression. This systematic review evaluated the current evidence for the effectiveness of interventions to improve subjective and/or objective social isolation for people with mental health problems. Primary outcomes of interest included loneliness, perceived social support, and objective social isolation., Methods: Three databases were searched for relevant randomised controlled trials (RCTs). Studies were included if they evaluated interventions for people with mental health problems and had objective and/or subjective social isolation (including loneliness) as their primary outcome, or as one of a number of outcomes with none identified as primary., Results: In total, 30 RCTs met the review's inclusion criteria: 15 included subjective social isolation as an outcome and 11 included objective social isolation. The remaining four evaluated both outcomes. There was considerable variability between trials in types of intervention and participants' characteristics. Significant results were reported in a minority of trials, but methodological limitations, such as small sample size, restricted conclusions from many studies., Conclusion: The evidence is not yet strong enough to make specific recommendations for practice. Preliminary evidence suggests that promising interventions may include cognitive modification for subjective social isolation, and interventions with mixed strategies and supported socialisation for objective social isolation. We highlight the need for more thorough, theory-driven intervention development and for well-designed and adequately powered RCTs.

Objective: To evaluate the time and number of laser beam passes required to make full-thickness skin incisions and extent of laser-induced tissue artifacts following use of a CO 2 laser at various settings., Sample: 24 skin specimens from six 5-month-old porcine carcasses., Procedures: 4 full-thickness skin specimens were harvested from the flank regions of each carcass within 30 minutes after euthanasia and randomly assigned to 4 treatment groups. Three 5-cm-long incisions were made in each specimen with a CO 2 laser (beam diameter, 0.4 mm) set to deliver a continuous wave of energy alone (groups 1 and 2) or in superpulse mode (groups 3 and 4) at 10 (groups 1 and 3) or 20 (groups 2 and 4) W of power. The time and number of passes required to achieve a full-thickness incision were recorded, and extent of laser-induced tissue artifact (as determined by histologic evaluation) was compared among the 4 groups., Results: Mean time required to make a full-thickness skin incision for groups 2 and 4 (power, 20 W) was significantly less than that for groups 1 and 3 (power, 10 W). Mean number of passes was lowest for group 2 (continuous wave at 20 W). Extent of laser-induced tissue artifact was greatest for group 4 (superpulse mode at 20 W)., Conclusions and Clinical Relevance: Results provided preliminary information regarding use of CO 2 lasers to make skin incisions in veterinary patients. In vivo studies are necessary to evaluate the effect of various CO 2 laser settings on tissue healing and patient outcome.

Background: Loneliness has not until recently been a prominent focus in research on outcomes of mental illness. The aim of this study was to determine whether loneliness at baseline predicts poor outcomes at 4-month follow-up for individuals who have experienced mental health crises. The outcomes in this study included overall symptom severity, affective symptoms, self-rated recovery and health-related quality of life., Methods: Our study reports a secondary analysis of data from a randomised controlled trial. The sample (n = 399) was taken from patients who received treatment from community crisis services. Respondents (n = 310) completed the follow-up measurement 4 months after baseline. Loneliness at baseline was assessed using an eight-item UCLA Loneliness Scale. The four mental health outcomes were measured at both baseline and follow-up. Two scales (or part thereof) assessed objective social isolation and neighbourhood social capital at baseline. Regression analyses were conducted to investigate longitudinal associations between loneliness at baseline and mental health outcomes at follow-up., Results: Loneliness at baseline was associated with all four mental health outcomes at 4-month follow-up, adjusting for psychosocial, socio-demographic and clinical characteristics. A one-point higher loneliness score was associated with 0.74-point (95% CI 0.45, 1.02) and 0.34-point (95% CI 0.21, 0.47) increase in overall symptom severity score and affective symptoms score respectively, and with 1.08-point (95% CI -1.45, - 0.71) and 1.27-point (95% CI -1.79, - 0.75) decrease in self-rated recovery score and health-related quality of life score respectively. Loneliness was a better predictor of clinical outcomes than objective social isolation and social capital, even though the associations with clinical outcomes were reduced and no longer statistically significant following adjustment for their baseline values. A significant association with quality of life persisted after adjustment for its baseline score., Conclusions: Greater loneliness at baseline predicted poorer health-related quality of life at follow-up. There were cross-sectional associations between loneliness and clinical outcomes, but their longitudinal relationship cannot be confirmed. Further research is needed to clearly establish their underpinning pathways. Reducing loneliness may be a promising target to improve recovery for mental health community crisis service users.

Objective: To determine if there is a difference in intra-abdominal pressure (IAP) among 3 anatomic body positions (right lateral, left lateral, and sternal recumbence) in apparently healthy dogs., Design: Prospective, observational study., Setting: University Veterinary Medical Teaching Hospital., Animals: Fourteen apparently healthy male dogs., Measurements and Main Results: After mild sedation with dexmedetomidine, a water manometer attached to a Foley urinary catheter was used to measure IAP in 3 different body positions in each dog. There was no significant difference in IAP between right lateral (3.87± 3.16 cm H 2 O), left lateral (4.45 ± 3.22 cm H 2 O), and sternal recumbence (4.04 ± 3.57 cm H 2 O)., Conclusions: Based on data from these 14 apparently healthy dogs, these 3 body positions can be used interchangeably for monitoring an individual dog. However, more research in dogs is needed to see if this conclusion holds true when IAP is abnormal., (© Veterinary Emergency and Critical Care Society 2020.)

A 3yr old spayed female Brittany was referred with a cylindrical mass on the right side of her face. Three months earlier, a small stone embedded in the right parotid duct was noted and removed through a ductal incision by the referring veterinarian. At referral, the dog's general physical condition was normal except for a cylindrical mass on the right cheek. Skull radiographs showed a possibly retained sialolith or dystrophic mineralization within the previous surgical site. Aspiration of the mass yielded a thick, yellow/tan, mucopurulent fluid. Cytology of the fluid demonstrated degenerative neutrophils without bacteria. The cylindrical mass was excised with a carbon dioxide laser. The caudal end of the mass was connected to the parotid salivary gland and the rostral one-third of the mass tapered to a point. The caudal end of the mass was ligated with 3-0 polydioxanone and excised immediately rostral to the ligation. Histopathology revealed that the mass was parotid duct ectasia. The dog completely recovered with some mild temporary facial paresis and had no recurrence of parotid duct ectasia at 4 mo follow-up. The case report describes a dog with an unusual parotid salivary duct ectasia caused by parotid duct sialolith removal.